ClinVar Miner

Submissions for variant NM_001035.3(RYR2):c.11497G>A (p.Asp3833Asn) (rs768711283)

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Total submissions: 3
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Color RCV000778055 SCV000914170 uncertain significance Cardiomyopathy 2018-06-26 criteria provided, single submitter clinical testing Variant of Uncertain Significance due to insufficient evidence: This variant is a missense variant located in the cytoplasmic domain of the RYR2 protein. Computational prediction tools and conservation analyses suggest that this variant may have deleterious impact on the protein function. Computational splicing tools suggest that this variant may not impact the RNA splicing. To our knowledge, functional assays have not been performed for this variant. This variant has been reported in an individual affected with hypertrophic cardiomyopathy who also carried a pathogenic variant in the MYBPC3 gene (PMID: 28771489). This variant has been identified in 8/189668 chromosomes in the general population by the Genome Aggregation Database (gnomAD). Available evidence is insufficient to determine the pathogenicity of this variant conclusively.
GeneDx RCV000182796 SCV000235182 uncertain significance not provided 2017-09-29 criteria provided, single submitter clinical testing The D3833N variant of uncertain significance in the RYR2 gene has not been published as pathogenic or been reported as benign to our knowledge. This variant is not observed at a significant frequency in large population cohorts (Lek et al., 2016). The D3833N variant is a semi-conservative amino acid substitution, which may impact secondary protein structure as these residues differ in some properties. This substitution occurs at a position where only amino acids with similar properties to aspartic acid (D) are tolerated across species, and in silico analysis predicts this variant is probably damaging to the protein structure/function. Furthermore, the D3833N variant is located in one of the three hot-spot regions of the RYR2 gene, where the majority of pathogenic missense variants occur (Medeiros-Domingo et al., 2009). However, this variant lacks observation in a significant number of affected individuals, segregation data, and functional evidence, which would further clarify its pathogenicity.
Invitae RCV000532433 SCV000637481 uncertain significance Catecholaminergic polymorphic ventricular tachycardia 2018-07-31 criteria provided, single submitter clinical testing This sequence change replaces aspartic acid with asparagine at codon 3833 of the RYR2 protein (p.Asp3833Asn). The aspartic acid residue is highly conserved and there is a small physicochemical difference between aspartic acid and asparagine. This variant is present in population databases (rs768711283, ExAC 0.01%). This variant has not been reported in the literature in individuals with RYR2-related disease. ClinVar contains an entry for this variant (Variation ID: 201312). This variant occurs within one of the three regions of the RYR2 gene (N-terminal domain, central domain, or channel region) where other pathogenic variants have been reported to cluster (PMID: 19926015). Algorithms developed to predict the effect of missense changes on protein structure and function do not agree on the potential impact of this missense change (SIFT: "Deleterious"; PolyPhen-2: "Possibly Damaging"; Align-GVGD: "Class C0"). In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance.

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